1. Field of the Invention
The present invention relates to specific N.sup.4 -acyl-.beta.-D-arabinofuranosylcytosine phosphates useful as water-soluble antileukemialagent for mice having high stability and also to specific N.sup.4 -acyl-1-.beta.-D-ribofuranosylcytosine phosphates which are intermediates in the production of the above-described arabinofuranosylyctosine phosphates.
2. Description of the Prior Art
Cytosine arabinoside is one of the most effective known antileukemial agents. However, since the biological half life of the medicament is short, due primarily to the fact that it is readily excreted and readily metabolized, complicated administration methods are requied to provide the full effect of the medicament to patients. Furthermore, since the medicament is readily converted into uracil arabinoside, which possesses no antileukemial activity, by deamination with deoxycytidine deaminase, the medicament is ineffective for patients having high deaminose activity.
2,2'-ANHYDROCYTOSINE ARABINOSIDE IS A DERIVATIVE OF CYTOSINE ARABINOSIDE WHICH POSSESSES IMPROVED SUSCEPTIBILITY TO THE DEAMINOSE (IT SHOWS HIGH RESISTANCE TO THE DEAMINOSE). While this medicament itself does not have antileukemial activity, it is gradually hydrolyzed in the body to form cytosine arabinoside, which exhibits antileukemial activity. This medicament is, however, quite readily excreted, and thus the greater part of the medicament is excreted before it is converted into the effective cytosine arabinoside. Effectively, the biological half life of this derivative is as short as that of cytosine arabinoside. Thus, to obtain sufficient effects from this derivative as a medicament, it is necessary to daily administer large amounts (e.g., 700 mg/kg) to mice.
The inventors previously performed various investigations to discover more effective antileukemial agents for mice by selecting materials which would prolong the life of mice infected by the leukemia L-1210, using the method developed by the Drugs Research & Development Department of the National Cancer Institute of the United States for screening antitumour agents and, as a result, the inventors found that N.sup.4 -acylcytosine arabinoside, where the acyl group is a straight-chain saturated or unsaturated aliphatic acyl group having at least 14 carbon atoms, shows an improved biological half life as compared with those of cytosine arabinoside and 2,2'-anhydrocytosine arabinoside.
That is, the acyl derivative of cytosine arabinoside, where the acyl group is an aliphatic acyl group or an aromatic acyl group having less than 12 carbon atoms, possesses an antileukemial activity for mice almost the same as or only slightly inferior to that of cytosine arabinoside, but the acyl derivative wherein the acyl group is an aliphatic acyl group having at least 14 carbon atoms possesses a much longer biological half life and has a high stability as compared with those of cytosine arabinoside and 2,2'-anhydrocytosine arabinoside.
Therefore, only one or two administrations of the acyl derivative greatly increases the life of mice infected with leukemia L-1210. However, the acyl derivatives have the disadvantage that N.sup.4 -acylcytosine arabinoside, which has a suitable oleophilicity and a high effect on mice infected with leukemia L-1210, is insoluble in water.
On the other hand, phosphoric acid esters and cyclic phosphoric acid esters of cytosine arabinoside are known. However, the phosphoric acid esters of cytosine arabinoside are inferior to cytosine arabinoside in antileukemial activity for mice, and while the cyclic phosphoric acid esters of cytosine arabinoside may have the same or a superior antiviral acitivity as compared by cytosine arabinoside, it is greatly inferior to the latter in activity against L-1210 leukemia in mice.
5'-Phosphoric acid esters of N.sup.4 -acylcytosine arabinoside are also known, in which the acyl group of the amino group at the 4-position thereof has 1 - 12 carbon atoms, as are 3',5'-cyclic phosphoric acid esters thereof, in which the acyl group of the amino group at the 4-position thereof has 1 - 18 carbon atoms. However, the phosphoric acid esters of the acyl derivative in which the acyl group has 1 - 12 carbon atoms and the cyclic phosphoric acid esters of the acyl derivative in which the acyl group has 1 - 18 carbon atoms possess substantially no antileukemial activity, although the latter may have an antiviral activity. Further, the cyclic phosphoric acid ester of the acyl derivative shows high hydrophobicity and is insoluble in water as compared with the phosphoric acid ester of the acyl derivative.